Nephrotoxicity of acyclovir and ganciclovir in rats

Abstract

Whole-kidney function and glomerular hemodynamics were evaluated after acute (50 mg/kg, iv, in bolus) and short-term chronic (50 mg mg/kg, ip, 5 days) acyclovir (ACV) and short-term chronic ganciclovir (Gan; 30 mg/kg, ip, 5 days) treatment in envolemic Munich-Wistar rats. The evaluation of whole-kidney function of the ACV groups showed a significant reduction in total GFR (0.96 +/- 0.10 to 0.28 +/- 0.02 mL/min in the acute group, P < 0.05, and 1.04 +/- 0.09 to 0.33 +/- 0.04 mL/min in the chronic group, P < 0.05) with a marked increase in total renal vascular resistance (TRVR) (33 +/- 5 to 122 +/- 26 mm Hg.min/mL in the acute group and 28 +/- 3 to 74 +/- 18 mm Hg.min/mL in the chronic group, P < 0.05) and a reduction in RPF (2.29 +/- 0.25 to 0.81 +/- 0.15 mL/min in the acute group and 2.57 +/- 0.36 to 1.30 +/- 0.40 mL/min in the chronic group, P < 0.05). Conversely, urinary flow (V') was unchanged (3.6 +/- 0.4 to 3.6 +/- 0.2 microL/min in the acute group) or elevated (3.7 +/- 0.6 to 6.6 +/- 1.4 microL/min in the chronic group, P < 0.05). The evaluation of glomerular hemodynamics after ACV treatment showed a reduction in single-nephron GFR (SNGFR) (46.4 +/- 5.3 to 26.2 +/- 3.4 nL/min in the acute group and 38.7 +/- 5.7 to 21.1 +/- 5.7 nL/min in the chronic group, P < 0.05), a significant elevation in total arteriolar resistance (RT) (2.90 +/- 0.44 to 4.94 +/- 0.77 x 10(10) dyn.s.cm-5 in the acute group and 3.72 +/- 0.45 to 9.00 +/- 2.40 x 10(10) dyn.s.cm-5 in the chronic group, P < 0.05) and a severe reduction in glomerular plasma flow rate (QA) (152.6 +/- 29.5 to 103.8 +/- 27.8 nL/min in the acute group and 149.1 +/- 29.8 to 68.5 +/- 10.0 nL/min in the chronic group, P < 0.05). However, the glomerular ultrafiltration coefficient, Kf, was changed only in the chronic group (0.1002 +/- 0.0165 to 0.0499 +/- 0.0090 nL/(s.mm Hg), P < 0.05). After Gan treatment, no changes were observed in GFR (1.04 +/- 0.09 to 0.96 +/- 0.08 mL/min, with the maintenance of RPF (2.57 +/- 0.36 to 2.66 +/- 0.34 mL/min) and a nonsignificant reduction in TRVR (28 +/- 3 to 20 +/- 3 mm Hg.min/mL. The short-term Gan treatment also showed a different pattern in glomerular hemodynamics by inducing an elevation in SNGFR (38.7 +/- 5.7 to 50.3 +/- 2.8 nL/min, P < 0.05) with no changes in QA (150 +/- 30 to 135 +/- 22 nL/min) and a mild vasodilation, RT (3.7 +/- 0.5 to 2.7 +/- 0.3 x 10(10) dyn.s.cm-5, P < 0.05) associated with an increment in Kf (0.1002 +/- 0.0165 to 0.2400 +/- 0.0700 nL/(s.mm Hg), P < 0.05). Thus, ACV induced acute renal failure by reducing GFR and SNGFR by an increase in TRVR and RT with a reduction in RPF and QA. Also, after short-term treatment with ACV, a reduction in Kf led to a reduction of SNGFR. On the other hand, Gan treatment did not induce acute renal failure by the adopted techniques.

Effect of ketoprofen on intravenous pharmacokinetics of ganciclovir in chukar partridges (Alectoris chukar)

“…Acyclovir is widely used in herpesvirus infections in animals, including birds (Greenacre, 2005; Plumb, 2011; Samorek‐Salamonowicz et al, 1987). However, because ganciclovir has advantages such as long elimination half‐life in cytomegalovirus‐infected cells, lower dose rate, and low nephrotoxic effect compared to acyclovir (Carmichael et al, 2013; Crumpacker, 1996; Dos Santos et al, 1997), it may have the potential use and advantages in infections caused by herpesviruses in partridges. Ganciclovir was used at a dose of 10 mg/kg in the treatment of ducks infected with duck hepatitis B virus (Luscombe et al, 1994; Niu et al, 1993).…”

Selenoacyclovir and Selenoganciclovir: Discovery of a New Template for Antiviral Agents

“…It can be also used as a substrate for CMV DNA polymerase and is incorporated into the viral DNA chain, resulting in the prevention of viral DNA synthesis . However, this drug is also associated with high cytotoxicity such as bone marrow suppression, hepatotoxicity, and nephrotoxicity . These drawbacks prompted us to design a new template for acyclic nucleoside drug development.…”